T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

项目摘要 近年来，癌症免疫疗法取得了长足的进步，但仍需要改进的方法来 在更多患者中实现更持久的反应。抑制性受体阻断 程序性死亡1（PD-1）使肿瘤反应性T细胞能够有效地识别和消除肿瘤， 这些患者是应答患者的子集，但许多患者对PD-1阻断具有抗性。为了提高响应率，我们 需要更好地了解导致治疗耐药性的机制。本项目的总体目标 是了解T细胞的作用-内在因素，有助于患者的反应与抵抗， PD-1封锁。我们将确定与阻断相关的信号通路和基因表达模式 特别关注T细胞受体（TCR）亲和力的作用。我们假设化妆品 肿瘤特异性T细胞的TCR亲和力的降低影响肿瘤抗原识别、活化信号传导和 下游基因表达，从而有助于患者对治疗的反应。分析这些参数 在患者样品和PD-1阻断的小鼠模型中， 对治疗的反应。在我们的第一个目标中，我们将分离和量化黑色素瘤的TCR结合特性， 来自PD-1阻断应答性和抗性患者的抗原特异性T细胞，以确定TCR亲和力如何影响PD-1阻断应答性和抗性患者的免疫应答。 谱影响PD-1阻断反应。在我们的第二个目标中，我们将使用蛋白质组学和基因组学分析， 患者抗原特异性T细胞产生PD-1阻断应答和抗性的整体特征。在我们 第三个目标是，我们将使用一组对相同抗原具有不同亲和力的黑素瘤患者来源的TCR 用于体外和体内实验，以确定TCR亲和力如何影响对PD-1阻断的反应。 总之，我们将确定黑色素瘤特异性T细胞的TCR亲和力对阻断黑色素瘤的作用。 并将提供证据支持基于TCR亲和力靶向特定T细胞， 联合治疗和基于TCR选择可能对PD-1阻断治疗有反应的患者 亲和谱。

PROJECT SUMMARY Cancer immunotherapy has made great strides in recent years, yet improved approaches are required to achieve more durable responses in a greater number of patients. Blockade of the inhibitory receptor programmed-death 1 (PD-1) enables tumor-reactive T cells to effectively recognize and eliminate tumors in a subset of responsive patients, but many patients are resistant to PD-1 blockade. To improve response rates, we need to better understand the mechanisms that lead to therapeutic resistance. The overall goal of this project is to understand the role of T cell–intrinsic factors that contribute to patient response versus resistance to PD-1 blockade. We will identify signaling pathways and gene-expression patterns associated with blockade response with a particular focus on the role of T-cell receptor (TCR) affinity. We hypothesize that the make-up of TCR affinities of tumor-specific T cells affects tumor antigen recognition, activation signaling, and downstream gene expression, thus contributing to patient response to therapy. Analysis of these parameters in patient samples and mouse models of PD-1 blockade will allow us to identify T cell properties characteristic of response to therapy. In our first aim we will isolate and quantify the TCR-binding properties of melanoma antigen-specific T cells from PD-1 blockade–responsive and –resistant patients to determine how TCR affinity profiles influence PD-1 blockade responses. In our second aim we will use proteomic and genomic analysis of patient antigen-specific T cells to develop a global signature of PD-1 blockade response and resistance. In our third aim we will use a panel of melanoma patient–derived TCRs with varying affinities for the same antigen for in vitro and in vivo experiments to determine how TCR affinity influences response to PD-1 blockade. Overall, we will determine the contribution of TCR affinities of melanoma-specific T cells to blockade resistance and will provide evidence to support the targeting of specific T cells based on TCR affinity for combination therapies and the selection of patients likely to respond to PD-1 blockade therapy based on TCR affinity profiles.